Summary Dopamine D1 receptors (D1Rs) in the dorsal striatum are hypothesized to play a major role in methamphetamine (Meth) addiction, and self-administration paradigms of Meth intake (clinically relevant models of Meth addiction) have reported that Meth self-administration increases D1R expression in the striatum and systemic D1R blockade decreases responding to Meth and reduces Meth seeking. Systemic D1 receptor antagonism in Meth experienced animals also prevented some aspects of maladaptive alterations; e.g. Meth-induced hyperphosphorylation of ERK1/2 in the striatum and Meth reward, indicating that enhancement of ERK1/2 by Meth is an intracellular signal transduction mechanism contributing to the maladaptive plasticity associated with reinforcing effects of Meth. These studies suggest that progressive increases in the intake of Meth over extended access schedules of reinforcement may lead to persistent neurobiological alterations in the striatum through aberrant increases in D1R expression and ERK1/2 activity. Therefore, the proposal will determine whether D1Rs and ERK1/2 activity in the dorsal striatum plays a role in establishing compulsive-like self-administration in animals experiencing Meth over extended access schedules of reinforcement. New evidence demonstrates that D1R signaling occurs in discrete plasmalemmal microdomains termed membrane/lipid rafts. Lipid rafts are enriched in cholesterol- and sphingolipid and the cholesterol binding and scaffolding protein caveolin-1 (Cav-1). Cav-1 is important in regulating D1R signaling, turnover and function. Therefore, we also seek to determine whether Cav-1 in D1R expressing neurons plays a role in mediating the maladaptive behavioral responses in compulsive Meth taking and seeking in Meth addicted animals. We will test these hypotheses using well-established rodent models of compulsive-like Meth self-administration and state-of-the-art genetic and pharmacological techniques to determine the role of D1Rs, ERK1/2 activity and Cav-1 in Meth addiction. Understanding the cellular and molecular mechanisms underlying Meth addiction in the dorsal striatum in animal models that demonstrate compulsive-like behavior has tremendous potential for identifying therapeutic interventions for reducing Meth addiction and maladaptive patterns of Meth seeking.